The present invention relates generally to intranasal delivery methods and dosage forms. More particularly, methods and dosage forms for the safe and reliable intranasal delivery of apomorphine to ameliorate erectile dysfunction in a mammal are provided.
Apomorphine is a potent dopamine receptor agonist which has a variety of uses. For example, it has been effectively used as an adjunctive medication in the treatment of Parkinson""s disease which is complicated by motor fluctuations (T. van Laar et al., Arch. Neurol., 49: 482-484 (1992)). In particular, apomorphine has been used for relieving xe2x80x9coff-periodxe2x80x9d symptoms in Parkinson patients with such response fluctuations. In the study by van Laar et al., the intranasally applied apomorphine used to achieve the results reportedly included an aqueous solution of apomorphine hydrochloride (HCL) at a concentration of 10 mg/ml. This formulation is also used for parenteral application and is published in different Pharmacopeia""s.
Also, U.S. Pat. No. 5,756,483 issued to Merkus (hereinafter xe2x80x9cthe ""483 patentxe2x80x9d) which is hereby incorporated by reference, discloses the intranasal delivery of a variety of compositions, including apomorphine in combination with a cyclodextrin and/or a polysaccharide and/or a sugar alcohol for treating Parkinson""s disease. The ""483 patent, however, discloses very narrow dosage ranges of 0.1 to 2 mg of apomorphine per nostril which is specifically tailored for the amelioration of the xe2x80x9coff-periodxe2x80x9d symptoms of Parkinson""s disease.
Further, U.S. Pat. No. 5,770,606 issued to El-Rashidy et al. (hereinafter xe2x80x9cthe ""606 patentxe2x80x9d), which is hereby incorporated by reference, discloses the delivery of apomorphine in a sublingual dosage unit for alleviating psychogenic impotence or erectile dysfunction with no substantial undesirable side effects. The ""606 patent further includes results from a study conducted by the inventors on the effect of apomorphine delivered intranasally on erectile dysfunction. The study suggested that intranasal delivery of apomorphine at concentrations of 2.5 mg to 3.5 mg was effective for eliciting an erection in patients suffering from erectile dysfunction, however, since the study participants suffered extensive and serious side effects including hypotension, nausea, vomiting, impaired vision, diaphoresis and ashen coloring, it was concluded that intranasal delivery of apomorphine to treat erectile dysfunction was insufficiently safe and reliable to be a viable commercial product.
Accordingly, it is one of the purposes of this invention, among others, to provide a safe and reliable intranasal delivery system for apomorphine that ensures delivery of therapeutic amounts of the drug into the bloodstream which is fast acting, easily administered and causes no substantial adverse side effects.
It has now been discovered that this and other purposes can be achieved by the present invention, which provides for a method for ameliorating male erectile dysfunction in a mammal. This method includes the nasal administration of a dopamine receptor agonist to the mammal before, during or after sexual activity in an amount sufficient to induce an erection without inducing substantial intolerable side effects in the mammal. Preferably, the dopamine receptor agonist is apomorphine.
The present invention also provides for a pharmaceutical composition for treating male erectile dysfunction in a mammal without causing substantial intolerable adverse side effects that includes a therapeutically effective amount of a dopamine receptor agonist in combination with a nasal delivery system. Preferably, the dopamine receptor agonist is selected from the group consisting of apomorphine, chemically modified equivalents and pharmaceutical salts thereof and even further preferably, the dopamine receptor agonist is apomorphine. The chemically modified equivalents of apomorphine preferably include a pro-drug. Further, it is preferable that apomorphine is dispersed in an aqueous or non-aqueous formulation.
In addition, the nasal delivery system of the pharmaceutical composition can include a buffer to maintain the pH of the dopamine receptor agonist, a pharmaceutically acceptable thickening agent and a humectant. The pharmaceutical composition can further include one or more pharmaceutical excipients and even further include a pharmaceutically acceptable preservative.
The buffer of the nasal delivery system can be selected from the group including acetate, citrate, prolamine, carbonate and phosphate buffers.
The thickening agent of the nasal delivery system can be selected from the group including methyl cellulose, xanthan gum, carboxymethyl cellulose, hydroxypropyl cellulose, carbomer, polyvinyl alcohol, alginates, acacia, chitosans and combinations thereof.
The humectant of the nasal delivery system can be selected from the group including sorbitol, glycerol, mineral oil, vegetable oil and combinations thereof.
The present invention also provides a method of treating erectile dysfunction in a male mammal including nasally administering a pharmaceutical composition including a therapeutically effective amount of a dopamine receptor agonist in combination with a nasal delivery system wherein the pharmaceutical composition does not cause substantial intolerable adverse side effects in the mammal.
The present invention also provides for a nasally administered pharmaceutical composition that includes a therapeutically effective amount of a dopamine receptor agonist dispersed in a buffer to maintain its pH, a pharmaceutically acceptable thickening agent and a humectant, wherein said nasally administered pharmaceutical composition does not cause substantial intolerable adverse side effects when administered to a mammal. The dopamine receptor agonist of the nasally administered pharmaceutical composition is selected from the group including apomorphine, chemically modified equivalents and pharmaceutical salts thereof. It is further preferable that chemically modified equivalents of apomorphine include a pro-drug.
The present invention also provides for a method of treating impotence and male erectile dysfunction in a human in need of such treatment including administering to a nasal membrane of the human an effective amount of a nasally administered pharmaceutical composition including a therapeutically effective amount of a dopamine receptor agonist dispersed in a buffer to maintain its pH, a pharmaceutically acceptable thickening agent and a humectant, wherein the nasally administered pharmaceutical composition does not cause substantial intolerable adverse side effects when administered to the human.
Another preferred method of the present invention also provides for treating male erectile dysfunction in a mammal without causing substantial intolerable adverse side effects. This method includes administering into a nasal cavity of the mammal a therapeutically effective dosage of a dopamine receptor agonist in combination with a nasal delivery system. The nasal delivery system includes a pharmaceutically acceptable buffer, a thickening agent and a humectant. The dopamine receptor agonist is selected from the group including apomorphine, chemically modified equivalents and pharmaceutical salts thereof Preferably, chemically modified equivalents of apomorphine include a pro-drug.
Another preferred method of the present invention is a method for administering a therapeutically effective amount of a dopamine receptor agonist to a mammal through a nasal membrane without causing substantial intolerable adverse side effects. This method includes delivering to the nasal membrane of a mammal a dopamine receptor agonist dispersed in a nasal delivery system which includes a pharmaceutically acceptable buffer, a thickening agent and a humectant. Preferably, the dopamine receptor agonist is effective for the treatment of male erectile dysfunction in a mammal.
The present invention also provides for an intranasal dosage unit for treating impotency or erectile dysfunction in a mammal which does not cause substantial intolerable adverse side effects. The dosage unit includes an effective amount of a dopamine receptor agonist in combination with an intranasal carrier. The intranasal carrier includes a buffer. The buffer pH is selected to enhance absorption of the dopamine receptor agonist and to produce an erection within about 60 minutes of administering the dosage unit to a nasal mucosa of the mammal. Preferably, an erection is produced within about 45 minutes, more preferably within about 30 minutes, most preferably within about 15 minutes, and even further preferably in less than about 15 minutes.
The intranasal carrier of the intranasal dosage unit is preferably an aqueous solution. Further, the aqueous solution can be selected from the group including aqueous gels, aqueous suspensions, aqueous liposomal dispersions, aqueous emulsions, aqueous microemulsions and combinations thereof.
Alternatively, the intranasal carrier of the intranasal dosage unit is a non-aqueous solution. The non-aqueous solution can be selected from a group including non-aqueous gels, non-aqueous suspensions, non-aqueous liposomal dispersions, non-aqueous emulsions and non-aqueous microemulsions and combinations thereof.
The intranasal carrier of the intranasal dosage unit can also be a combination of an aqueous solution and a non-aqueous solution.
Alternatively, the carrier of the intranasal dosage unit is a powder formulation. The powder formulation can be selected from a group including simple powder mixtures, powder microspheres, coated powder microspheres, liposomal dispersions and combinations thereof. Preferably, the powder formulation is powder microspheres. The powder microspheres are preferably formed from various polysaccharides and celluloses selected from the group including starch, methylcellulose, xanthan gum, carboxymethylcellulose, hydroxypropyl cellulose, carbomer, alginate polyvinyl alcohol, acacia, chitosans and combinations thereof.
The intranasal dosage unit can also include an excipient having bio-adhesive properties. Preferably, the buffer of the intranasal dosage unit is selected to have a pH of from about 3 to about 10 and more preferably from about 3.5 to 7.0.
Preferably, the intranasal dosage unit includes a humectant. A humectant can be selected from the group consisting of soothing agents, membrane conditioners, sweeteners and combinations thereof.
The present invention also provides for a nasally administered pharmaceutical composition for treating male erectile dysfunction in a mammal including a therapeutically effective amount of a dopamine receptor agonist which has been dispersed in a system to improve its solubility. The dopamine receptor agonist of this composition is selected from the group consisting of apomorphine, chemically modified equivalents and pharmaceutical salts thereof. The system of this composition includes one of the following or combinations thereof: a glycol derivative; a sugar alcohol; glycerin; propylene glycol and glycerin; polyethylene glycol 400; ascorbic acid and water; sodium ascorbate and water; or sodium metabisulfite and water. Preferred glycol derivatives include propylene glycol and polyethylene glycol. Preferred sugar alcohols include mannitol and xylitol.
The present invention also provides for a nasally administered pharmaceutical composition for treating male erectile dysfunction in a mammal including a therapeutically effective amount of a dopamine receptor agonist which has been dispersed in a system to improve its stability. The dopamine receptor agonist of this composition is selected from the group consisting of apomorphine, chemically modified equivalents and pharmaceutical salts thereof. The system of this composition includes one of the following or combinations thereof: a glycol derivative; a sugar alcohol; glycerin; propylene glycol and glycerin; polyethylene glycol 400; ascorbic acid and water; sodium ascorbate and water; or sodium metabisulfite and water. Preferred glycol derivatives include propylene glycol and polyethylene glycol. Preferred sugar alcohols include mannitol and xylitol.
These and other advantages of the present invention will be appreciated from the detailed description and examples which are set forth herein. The detailed description and examples enhance the understanding of the invention, but are not intended to limit the scope of the invention.